Herein is proposed a novel, general method for the practical total synthesis of the epipodophyllotoxin antitumor agents: VM-26 and VP-16-213. These two compounds have shown acceptable toxicity levels in phase I clinical trials and some useful therapeutic benefit against Hodgkin's disease. It has been suggested that VM-26 might be used routinely for clinical treatment of Hodgkin's disease. VP-16-213 has been reported to be one of the most effective plant compounds against the L1210 tumor ever tested. Thus our objective is the synthesis of these antineoplastic agents and their structural analogues which may have higher potential as cancer chemotherapeutic agents than these two drugs. The proposed synthetic route to these compounds involves a totally regio- and stereospecific approach to the construction of the molecular framework. The key step of this pathway is an intramolecular Diels-Alder reaction between appropriately substituted sections of the key compound which are held in the correct orientation for this reaction (syn-endo-transition state) by a suitably chosen bridge of atoms. In this manner the entire tetrahydronaphthalene skeleton of these important molecules can be assembled in one synthetic step in such a way that all of the substituent groups on the saturated ring are formed with the correct regio- and stereochemistry. This concept of utilizing an intramolecular Diels-Alder reaction instead of an intermolecular one for the construction of highly functionalized polycyclic molecules is quite general and should be of great practical use in the field of organic synthesis.